.beta.-Adrenergic blockers were first reported to be useful for the therapeutic treatment of glaucoma in 1967 [Phillips et al, Brit. J. Ophthal., 1967, 51, 222]. In 1978 timolol was approved for market use and since that time the drug has become very popular with ophthalmologists as an effective antiglaucoma agent. Recently, however, a vast number of serious cardiovascular, respiratory, CNS and ocular side effects secondary to topical ocular timolol administration has been reported [Ahmad, The Lancet, 1979, 2, 1028; Buskirk, Ophthalmology, 1980, 87, 447; Mishra et al, J. Anaesth., 1983, 55, 897; and Linkewich et al, Am. J. Hosp. Pharm., 1981, 38, 699]. Currently, timolol is no longer the sole .beta.-blocker used to treat glaucoma. Befanolol, carteolol and metipranolol were introduced recently and a number of other newer .beta.-adrenergic antagonists (e.g., L-bunolol, betaxolol, celiprolol, cetamolol etc.) are currently under investigation as antiglaucoma agents.
It became desirable to design an antiglaucoma drug which could be delivered to the eye compartments in a sustained and controlled manner with minimal systemic absorption and/or no systemic side effects.
It was previously found that after topical application to the eye, esters of adrenalone but not adrenalone itself can be converted via a reduction-hydrolysis sequence to deliver adrenaline (epinephrine) at the iris-ciliary body, the desired site of action [Bodor et al, Exp. Eye. Res., 1984, 38, 621]. Research was conducted to ascertain whether lipophilic ketones could also be reduced in the iris-ciliary body.
It was hypothesized that ketone precursors of .beta.-blockers which are also .beta.-hydroxylamines like adrenaline could then possibly be converted to the active .beta.-blockers in the iris-ciliary body by a reductive process. Various attempts, however, to synthesize the ketones corresponding to a number of .beta.-blockers (i.e., propranolol, timolol, carteolol etc.) failed, due to the chemical instability of these .beta.-amino-ketone ethers.
A few ketones corresponding to .beta.-blockers or analogs thereof have been previously described in the art. Thus, Ahmed et al, J. Pharm. Belg. 37(3), 214-217 (1982), abstracted in Chem. Abst., Vol. 97, 188158n (1982), have described reacting N-chlorosuccinimide and N-bromosuccinimide with propranolol hydrochloride in an attempt to develop a titrimetic method for detection of propranolol. Obtained as a reaction product of propranolol hydrochloride with N-chlorosuccinimide were succinimide and a dichlorinated ketone of the formula ##STR2## Further, French Patent Publication No. 2070067 published Sept. 10, 1971 has described, as intermediates to .beta.-blockers, ketones of the formula ##STR3## wherein Y is a lower alkyl or lower hydroxyalkyl radical and X is chloro, lower alkyl, lower alkoxy, phenyl, benzyl, morpholino, piperidyl, hydroxypiperidyl or N-(lower alkyl)-piperazinyl. The patent teaches reduction by chemical means or by fermentation of the ketones to the desired final products. Specific ketones named in the French document are 3-morpholino-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole, 3-chloro-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole, 3-chloro-4-(3-isopropylamino-2-oxopropoxy)-1,2,5-thiadiazole, 3-ethyl-4-(3-isopropylamino-2-oxopropoxy)-1,2,5-thiadiazole, 3-ethyl-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole, 3-ethyl-4-[3-(1,1-dimethyl-2-hydroxyethylamino)-2-oxopropoxy]-1,2,5-thiadi azole, 3-ethoxy-4-(3-isopropylamino-2-oxopropoxy)-1,2,5-thiadiazole, 3-ethoxy-4-(3-tert-butylamino-2-oxopropoxy-1,2,5-thiadiazole, 3-ethoxy-4-[3-(2,2-dimethylpropylamino)-2-oxopropoxy]-1,2,5-thiadiazole, 3-phenyl-4-(3-isopropylamino-2-oxopropoxy)-1,2,5-thiadiazole, 3-phenyl-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole and 3-benzyl-4-(3-tert-butylamino-2-oxopropoxy)-1,2,5-thiadiazole. Neither reference has disclosed any biological activity for the ketones, however.
It is an object of the present invention to provide novel hydrolytically sensitive precursors of the ketone precursors of the .beta.-adrenergic blocking .beta.-hydroxylamines which are readily converted to the active .beta.-blockers in the iris-ciliary body by combined hydrolytic and reductive processes.